Bonfrate Leonilde, Procino Giuseppe, Wang David Q-H, Svelto Maria, Portincasa Piero
Department of Biomedical Sciences and Human Oncology, Internal Medicine, University Medical School, Bari, Italy.
J Cell Mol Med. 2015 Feb;19(2):265-82. doi: 10.1111/jcmm.12422. Epub 2015 Jan 16.
Statins competitively inhibit hepatic 3-hydroxy-3-methylglutaryl-coenzyme A reductase, resulting in reduced plasma total and low-density lipoprotein cholesterol levels. Recently, it has been shown that statins exert additional 'pleiotropic' effects by increasing expression levels of the membrane water channels aquaporin 2 (AQP2). AQP2 is localized mainly in the kidney and plays a critical role in determining cellular water content. This additional effect is independent of cholesterol homoeostasis, and depends on depletion of mevalonate-derived intermediates of sterol synthetic pathways, i.e. farnesylpyrophosphate and geranylgeranylpyrophosphate. By up-regulating the expression levels of AQP2, statins increase water reabsorption by the kidney, thus opening up a new avenue in treating patients with nephrogenic diabetes insipidus (NDI), a hereditary disease that yet lacks high-powered and limited side effects therapy. Aspects related to water balance determined by AQP2 in the kidney, as well as standard and novel therapeutic strategies of NDI are discussed.
他汀类药物竞争性抑制肝脏3-羟基-3-甲基戊二酰辅酶A还原酶，从而降低血浆总胆固醇和低密度脂蛋白胆固醇水平。最近研究表明，他汀类药物通过增加膜水通道水通道蛋白2（AQP2）的表达水平发挥额外的“多效性”作用。AQP2主要定位于肾脏，在决定细胞含水量方面起关键作用。这种额外作用独立于胆固醇稳态，且取决于甾醇合成途径中甲羟戊酸衍生中间体（即法尼基焦磷酸和香叶基香叶基焦磷酸）的消耗。通过上调AQP2的表达水平，他汀类药物增加肾脏对水的重吸收，从而为治疗肾性尿崩症（NDI，一种缺乏高效且副作用有限的治疗方法的遗传性疾病）的患者开辟了一条新途径。本文讨论了与肾脏中由AQP2决定的水平衡相关的方面，以及NDI的标准和新型治疗策略。
